Process analytical chemistry.
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Chemistry Techniques, Analytical↗
Biomedical subjects
A Ullman
Publications and source records attributed to A Ullman.
The inhaled Steroid Treatment as Regular Therapy in early asthma (START) study: rationale and design.
Although the beneficial effects of treatment with inhaled steroids in asthma are widely accepted, the role of early intervention in patients with mild asthma remains unsettled. Conventional efficacy trials are often of short duration and involve highly selected patient populations that exclude many patients typical of those encountered in routine clinical practice. Hence, a large "real-world" effectiveness study is needed to evaluate the benefits of early intervention with inhaled steroids in patients with mild, persistent asthma. In the START (inhaled Steroid Treatment As Regular Therapy in early asthma) study, patients ages 6-60 years, from 31 countries and districts worldwide with mild persistent asthma, have been randomized to once-daily treatment with budesonide, 200 microg (for patients < 11 years) or 400 microg (for patients > or = 11 years), or placebo via Turbuhaler for 3 years. The double-blind treatment period will be followed by a 2-year period of open budesonide treatment. Throughout the study, other asthma medication including glucocorticosteroids can be given as judged appropriate by the investigator. Lung function will be measured by spirometry using standardized techniques at 3-month intervals throughout the study, and bronchodilator reversibility will be measured annually. The primary outcome measures are the time to the first severe asthma-related event during the first 3 years of the study and the change in postbronchodilator forced expiratory volume in 1 second (FEV(1)) from baseline during the entire 5-year study period. These measures have been chosen to reflect the progression of mild asthma toward more severe asthma and the extent of irreversible airflow limitation, which should reflect the degree of airway remodeling.
Acute Disease↗
Adding formoterol to budesonide in moderate asthma--health economic results from the FACET study.
The FACET (Formoterol and Corticosteroid Establishing Therapy) study established that there is a clear clinical benefit in adding formoterol to budesonide therapy in patients who have persistent symptoms of asthma despite treatment with low to moderate doses of an inhaled corticosteroid. We combined the clinical results from the FACET study with an expert survey on average resource use in connection with mild and severe asthma exacerbations in the U.K., Sweden and Spain. The primary objective of this study was to assess the health economics of adding the inhaled long-acting beta2-agonist formoterol to the inhaled corticosteroid budesonide in the treatment of asthma. The extra costs of adding the inhaled beta2-agonist formoterol to the corticosteroid budesonide in asthmatic patients in Sweden were offset by savings from reduced use of resources for exacerbations. For Spain the picture was mixed. Adding formoterol to low dose budesonide generated savings, whereas for moderate doses of budesonide about 75% of the extra formoterol costs could be recouped. In the U.K., other savings offset about half of the extra cost of formoterol. All cost-effectiveness ratios are within accepted cost-effectiveness ranges reported from previous studies. If productivity losses were included, there were net savings in all three countries, ranging from Euro 267-1183 per patient per year. In conclusion, adding the inhaled, long-acting beta2-agonist formoterol to low-moderate doses of the inhaled corticosteroid budesonide generated significant gains in all outcome measures with partial or complete offset of costs. Adding formoterol to budesonide can thus be considered to be cost-effective.
Acute Disease↗
Strategies for target identification.
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Asthma↗
Exacerbations of asthma: a descriptive study of 425 severe exacerbations. The FACET International Study Group.
The identification, prevention, and prompt treatment of exacerbations are major objectives of asthma management. We looked at change in PEF, symptoms, and use of rescue beta-agonists during the 425 severe exacerbations that occurred during a 12-mo parallel group study (FACET) in which low and high doses of budesonide with and without formoterol were compared in patients with asthma. Oral corticosteroids were prescribed for severe exacerbations, the main study end point, defined as the need for a course of oral corticosteroids (n = 311) or a reduction in morning PEF of > 30% on two consecutive days. PEF, symptoms, and bronchodilator use over the 14 d before and after the exacerbation were obtained from diary cards. Exacerbations were characterized by a gradual fall in PEF over several days, followed by more rapid changes over 2 to 3 d; an increase in symptoms and rescue beta-agonist use occurred in parallel, and both the severity and time course of the changes were similar in all treatment groups. Exacerbations identified by the need for oral corticosteroids were associated with more symptoms and smaller changes in PEF than those identified on the basis of PEF criteria. Female sex was the main patient characteristic associated with an increased risk of having a severe exacerbation. Exacerbations may be characterized predominantly by change in symptoms or change in PEF, but the pattern was not affected by the dose of inhaled corticosteroid or by whether the patient was taking formoterol.
Adolescent↗
Asthma quality of life during 1 year of treatment with budesonide with or without formoterol.
The Formoterol and Corticosteroids Establishing Therapy (FACET) study has provided the first opportunity to examine the long-term effects of inhaled steroids and long-acting beta2-agonists on asthma-specific quality of life. The objectives of the present study were to: evaluate the effects of long-term (1 yr) formoterol and increasing doses of budesonide on asthma quality of life; 2) to determine whether initial improvements in quality of life are sustained when improvements in clinical indices persist; and 3) to evaluate the long-term relationship between changes in clinical indices and changes in quality of life. Of the 852 asthmatic adults enrolled, 470 from five countries participated in this quality of life evaluation. After a 4-week run-in on 1,600 microg budesonide, patients were randomized to either 200 microg (Bud200) or 800 microg budesonide (Bud800) in combination with either 24 microg formoterol (F) or placebo daily for 1 yr. The Asthma Quality of Life Questionnaire (AQLQ) was completed and conventional clinical indices measured at enrolment and randomization and on seven occasions during the following 12 months. During the run-in, there was an improvement in AQLQ score (changes (delta) in overall score approximately 0.50; p<0.0001). After randomization, there was a further improvement in the Bud800+F group (delta=0.21; p=0.028). One month post-randomization, improvements in all groups stabilized and were sustained throughout the 12 months in a pattern very similar to that observed for the conventional clinical indices. The correlation of individual patient changes in clinical indices and changes in AQLQ score during the 12-month randomized period were weak to moderate (maximum r=0.51). Improvements in quality of life, which were greatest in the 800 microg budesonide plus 24 microg formoterol group, were sustained throughout the 12 months in a similar manner to the clinical indices. Long-term changes in conventional clinical indices cannot be used to predict the effect of treatment on individual patient experience.
Adrenergic beta-Agonists↗
[Budesonide is a safe inhalation steroid].
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Administration, Inhalation↗
Effect of inhaled formoterol and budesonide on exacerbations of asthma. Formoterol and Corticosteroids Establishing Therapy (FACET) International Study Group.
BACKGROUND: The role of long-acting, inhaled beta2-agonists in treating asthma is uncertain. In a double-blind study, we evaluated the effects of adding inhaled formoterol to both lower and higher doses of the inhaled glucocorticoid budesonide. METHODS: After a four-week run-in period of treatment with budesonide (800 microg twice daily), 852 patients being treated with glucocorticoids were randomly assigned to one of four treatments given twice daily by means of a dry-powder inhaler (Turbuhaler): 100 microg of budesonide plus placebo, 100 microg of budesonide plus 12 microg of formoterol, 400 microg of budesonide plus placebo, or 400 microg of budesonide plus 12 microg of formoterol. Terbutaline was permitted as needed. Treatment continued for one year; we compared the frequency of exacerbations of asthma, symptoms, and lung function in the four groups. A severe exacerbation was defined by the need for oral glucocorticoids or a decrease in the peak flow to more than 30 percent below the base-line value on two consecutive days. RESULTS: The rates of severe and mild exacerbations were reduced by 26 percent and 40 percent, respectively, when formoterol was added to the lower dose of budesonide. The higher dose of budesonide alone reduced the rates of severe and mild exacerbations by 49 percent and 37 percent, respectively. Patients treated with formoterol and the higher dose of budesonide had the greatest reductions -- 63 percent and 62 percent, respectively. Symptoms of asthma and lung function improved with both formoterol and the higher dose of budesonide, but the improvements with formoterol were greater. CONCLUSIONS: In patients who have persistent symptoms of asthma despite treatment with inhaled glucocorticoids, the addition of formoterol to budesonide therapy or the use of a higher dose of budesonide may be beneficial. The addition of formoterol to budesonide therapy improves symptoms and lung function without lessening the control of asthma.
Administration, Inhalation↗
Differences in bronchodilating potency of salbutamol in Turbuhaler as compared with a pressurized metered-dose inhaler formulation in patients with reversible airway obstruction.
Two studies are presented, with the aim of establishing the dose potency ratio for salbutamol given via Turbuhaler and via a pressurized metered-dose inhaler (pMDI). Both studies were of a double-blind, randomized design. Outpatients with mild-to-moderate chronic reversible airway obstruction were given single doses of salbutamol administered via Turbuhaler and via pMDI. Efficacy and safety variables were measured before and during 6 h after each dose. The first study was a four-way crossover study including 12 patients. The salbutamol doses given were: 50, 100 and 2x100 microg via Turbuhaler and 2x100 microg via pMDI (Ventolin). The study showed that 2x100 microg of salbutamol inhaled via Turbuhaler is more potent than 2x100 microg salbutamol inhaled via a pMDI, and that 100 microg salbutamol via Turbuhaler is at least as potent as 2x100 microg salbutamol inhaled via a pMDI. The second study including 50 patients was a placebo-controlled five-way crossover, study. Two doses of salbutamol via Turbuhaler, 50 and 2x100 microg, and via pMDI, 100 and 2x200 microg, were given. There was a dose-dependent response in forced expiratory volume in one second (FEV1) for both inhalers. Adjusted for differences in baseline FEV1 values, the estimated relative dose potency for Turbuhaler versus pMDI was 1.98:1 (95% confidence interval 12-3.2). These studies showed that the same bronchodilating effect can be achieved when half the dose of salbutamol given via a conventional pressurized metered-dose inhaler is given via Turbuhaler.
Administration, Inhalation↗
Formoterol inhaled as dry powder or via pressurized metered-dose inhaler in a cumulative dose-response study.
Formoterol administered by a dry-powder (DP) capsule inhaler was compared with a pressurized metered-dose inhaler (pMDI) with regard to bronchodilating and systemic effects. The study used a double-blind, crossover, double-dummy technique. Twelve patients with moderate reversible asthma in a stable phase were examined on two separate study days, and the inhalers were given in randomized order. After baseline measurements, increasing doses of formoterol were given at intervals of 75 min. FEV1 and heart rate and tremor measurements were repeated after each dose, and the doses were 12 + 12 + 24 + 48 micrograms, giving a total dose of 96 micrograms. The peak expiratory flow rate (PEFR) was recorded in the morning before the first dose, after the last dose, and then repeatedly at home until 19 h after the last dose. There was an equal increase in ventilatory capacity at each dose level, independent of inhaler device. Repeated PEFR measurements after the last dose did not reveal any differences in duration of effect. There was a slight but statistically significant increase in heart rate and tremor after the highest doses of the DP formulation compared to the pMDI. These systemic effects can probably be explained by the reduced oral deposition of the aerosol caused by using a spacer. This study indicates that the DP and pMDI formulations of formoterol are equipotent in bronchodilation.
Administration, Inhalation↗
Assessment of the relative systemic potency of inhaled fluticasone and budesonide.
Studies using dry powder devices have suggested that fluticasone propionate (FP) has a greater systemic effect than budesonide (BUD). The aim of the present study was to investigate and compare the relative systemic potency of FP and BUD from their respective pressurized metered-dose inhalers (pMDIs). A placebo-controlled, open, randomized, cross-over study was conducted in 21 healthy male volunteers. Placebo, BUD (200, 400 and 1,000 micrograms b.i.d.) and FP (200, 375 and 1,000 micrograms b.i.d.) were inhaled for 4 days, with a wash-out period of at least 3 days between treatments. Blood samples for cortisol analysis were drawn during the last 24 h of each treatment period. Cortisol levels, measured as 24 h pooled plasma cortisol, were statistically significantly lower (p = 0.0001) for all dose levels during FP pMDI treatment (21, 39 and 84% suppression from placebo) than during BUD pMDI treatment (1, 3 and 27% suppression from placebo). The relative systemic potency FP:BUD was 3.7:1 (95% confidence interval (95% CI) 2.9-4.8)). The relative systemic potency based on the single 08:00 h samples was 5.2:1 (95% CI 3.0-9.3). In conclusion, in healthy male volunteers using pressurized metered-dose inhalers, fluticasone propionate was shown to have a stronger systemic effect than budesonide.
Administration, Inhalation↗
beta-Adrenoceptor agonists in future asthma therapy.
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Administration, Inhalation↗
Morphine-sparing effect of diclofenac in cancer pain.
The effectiveness of diclofenac 50 mg t.i.d. as additive treatment to parenteral patient-controlled administration therapy (PCAT) with morphine in cancer pain has been investigated in a double-blind study. In the fifteen patients who completed the study, morphine i.v. was titrated to optimal pain relief over 5 days. The mean total morphine consumption was significantly reduced during diclofenac administration (82.8 mg morphine per day) compared to placebo (95.0 mg morphine per day). The reduction in mean morphine consumption during active treatment with diclofenac was independent of the initial dose of self-titrated morphine. Pain, self-assessed according to VAS, tended to be lower during the diclofenac period, although the difference did not reach statistical significance. No adverse events were recorded among the 15 patients who completed the study. The present findings show that a non-steroidal anti-inflammatory agent, such as diclofenac, has a morphine-sparing effect in morphine-treated patients with cancer pain.
Adult↗
Non-adrenergic, non-cholinergic neural activation in guinea-pig bronchi: powerful and frequency-dependent stabilizing effect on tone.
1. We examined non-adrenergic, non-cholinergic (NANC) stimulation for its stabilizing effect on bronchial smooth-muscle tone with respect to its regulatory power and the effect of variations in neural impulse frequency. 2. The guinea-pig isolated main bronchus (n = 4-12) was pretreated with indomethacin (10 microM) and incubated with atropine (1 microM) and guanethidine (10 microM). Electrical field stimulation (EFS: 1200 mA, 0.5 ms, 240 s) was applied at various levels of tone prior to EFS: first without tone, then at a moderate tone induced by histamine (0.3 microM) and, finally, at a high tone induced by histamine (6 microM). Three different stimulation frequencies (1, 3 or 10 Hz) were used in order to produce moderate to near-maximum contractile and relaxant NANC neural responses. Both the contractile and the relaxant NANC responses were tetrodotoxin-sensitive in the guinea-pig isolated main bronchus (3 Hz). 3. Without tone prior to EFS, NANC activation (1, 3 or 10 Hz) induced a pronounced contractile response. At a moderate level of tone prior to EFS, NANC activation induced a less pronounced contractile response. At the highest level of tone prior to EFS, NANC activation induced a relaxant response. All these NANC responses adjusted the tone towards a similar level and this 'stabilization level' was 56(6)% at 1 Hz, 65(3)% at 3 Hz and 56(5)% at 10 Hz, expressed as a percentage of the maximum histamine-induced (0.1 mM) tone in each airway preparation. 4. There was a difference of approximately 90% of maximum between the highest and the lowest tone level prior to NANC activation. This difference was reduced by the converging contractile and relaxantNANC responses and the magnitude of this 'convergence effect' was 40(8)% at 1 Hz, 72(4)% at 3 Hz and 90(2)% at 10 Hz.5. These findings indicate that NANC neural activation stabilizes bronchial smooth-muscle tone via a contraction when the tone is low prior to activation and via a relaxation when the tone is high prior to activation. The NANC stabilizing effect on tone appears to be powerful and its magnitude can be controlled by the neural impulse frequency. The level of tone towards which the NANC responses converge does not appear to be markedly altered by variations in the impulse frequency. Our findings are consistent with a regulatory role for NANC responses in the control of bronchial smooth-muscle tone.
Animals↗
The NANC system as a stabilizer of airway smooth-muscle tone.
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Animals↗
Salmeterol, formoterol, and salbutamol in the isolated guinea pig trachea: differences in maximum relaxant effect and potency but not in functional antagonism.
BACKGROUND: Formoterol and salmeterol are new long acting beta 2 adrenoceptor agonists. The maximum relaxant effect, potency and functional antagonism against carbachol induced contraction for salmeterol, formoterol and salbutamol have been compared in the guinea pig isolated trachea. In addition, the possibility of inducing a non-beta adrenoceptor mediated relaxation by salmeterol was studied. METHODS: Concentration response experiments were conducted with isolated tracheal preparations (n = 4-6 in all experiments), precontracted by carbachol to cause either 40% (60 nmol/l), 80% (0.3 mumol/l) or 100% (3 mumol/l, supramaximal) of the maximum contraction. Each beta agonist was added cumulatively at each level of precontraction. Additional cumulative concentration response experiments were conducted for salmeterol alone at the highest level of precontraction, with and without beta blockade by sotalol (1 mmol/l). With the drug concentrations which produced the maximum response and the highest level of precontraction, the relaxation of formoterol (10 nmol/l) and salmeterol (1 mumol/l) was also compared non-cumulatively. Finally, with the corresponding drug concentrations and precontraction, the relaxant effect was compared for formoterol (10 nmol/l) in salmeterol relaxed airways with that of salmeterol (1 mumol/l) in formoterol relaxed airways. RESULTS: The increase in carbachol concentration from 60 nmol/l to 3 mumol/l induced a rightward shift in the mean (SE) concentration (log steps) causing 50% maximum relaxation for salmeterol (0.73 (0.17)), formoterol (0.85 (0.18)), and salbutamol (1.13 (0.11)). Significant differences in the maximum relaxant effect were shown at the highest level of precontraction only, with a remaining active tension of percentage precontraction of 27% (4%) for 1 mumol/l salbutamol and 35% (3%) for 10 nmol/l formoterol compared with 50% (2%) for 1 mumol/l salmeterol. The rank order of potency was: formoterol > salbutamol approximately salmeterol at all levels of precontraction (-log EC50: 9.32 (0.05) for formoterol, 7.82 (0.08) for salbutamol, and 7.50 (0.13) for salmeterol at 80% maximum precontraction). Beta blockade by sotalol (1 mmol/l) significantly inhibited the relaxation induced by salmeterol (1 mumol/l) (remaining active tension: 104% (1%) v 71% (11%) of precontraction) but not the relaxation induced by salmeterol (10 mumol/l) (remaining active tension: 75% (5%) v 71% (12%) of precontraction). In the non-cumulative experiments, formoterol displayed more relaxant effect than salmeterol (remaining active tension: 51% (6%) v 65% (6%) of precontraction). Finally, formoterol significantly relaxed salmeterol relaxed airways (relaxant effect: 22% (8%) of precontraction) whereas there was no significant response to salmeterol in formoterol relaxed airways (relaxant effect: 5% (12%) of precontraction). CONCLUSIONS: In the guinea pig isolated trachea, formoterol and salbutamol produce more relaxant effect than salmeterol, suggesting that salmeterol is a partial beta 2 agonist. Very high concentrations of salmeterol may induce non-beta adrenoceptor mediated relaxation. Formoterol is more potent than both salbutamol and salmeterol. There is no pronounced difference in the magnitude of antagonism against carbachol induced contractions between salmeterol, formoterol, and salbutamol.
Adrenergic beta-Agonists↗
Nonadrenergic, noncholinergic responses stabilize smooth muscle tone, with and without parasympathetic activation, in guinea-pig isolated airways.
In guinea-pig isolated airways, nonadrenergic, noncholinergic (NANC) neural responses converge towards a similar level of smooth muscle tone, via a contraction when the tone is low prior to stimulation, and via a relaxation when the tone is high prior to stimulation. We wanted to assess the effect of simultaneous parasympathetic activation on these converging NANC responses, with and without the addition of sympathetic activation. In guinea-pig isolated airways, the spontaneous airway tone was initially abolished by indomethacin (10 microM). In one series, adrenergic depletion by guanethidine (10 microM) was then established, with and without cholinergic blockade by atropine (1 microM). In another series, either cholinergic blockade by atropine (1 microM) or no blockade was utilized. Responses to electrical field stimulation (1,200 mA, 0.5 ms, 3 Hz for 240 s) were studied with no induced tone, at a moderate (0.3 microM) and at a near-maximum (6 microM), histamine-induced tone. The mean level of the tonus equilibrium (% of maximum tone) was higher with the simultaneous NANC and parasympathetic activation than with NANC activation alone (75% compared with 44%, in the main bronchus, n = 8). The level of the tonus equilibrium was also higher with the simultaneous NANC, sympathetic and parasympathetic activation than with NANC and sympathetic activation only (49% compared with 21%, in the main bronchus, n = 8). The pattern was similar in the distal trachea. In conclusion, NANC neural responses can stabilize smooth muscle tone, and this stabilizing effect can be modulated by both parasympathetic and sympathetic activation, in guinea-pig isolated airways.
Animals↗
Twelve months, treatment with inhaled salmeterol in asthmatic patients. Effects on beta 2-receptor function and inflammatory cells.
Salmeterol is a new beta 2-receptor agonist with a prolonged duration of action after inhalation, exceeding 12 h in most patients. We have performed a 12-month open follow-up study on 11 patients with reversible asthma. All patients were given salmeterol inhalations (50 micrograms twice daily). Additional asthma treatment included inhaled corticosteroids in all patients, and oral slow-release theophylline or beta 2-receptor agonists in a minority of patients (3 and 1, respectively). Before salmeterol treatment was initiated and after 3, 6, 9 and 12 months of salmeterol treatment, a cumulative dose-response curve to inhaled salbutamol (100, 300 and 900 micrograms) was performed, and FEV1 measured. We also evaluated the effect of each salbutamol dose on finger tremor, systemic blood pressure and heart rate. Blood tests, including white blood count and electrolytes, were taken at each visit. After salmeterol treatment was initiated, morning FEV1, measured before the morning asthma medication, was significantly improved (p < 0.05). The responsiveness to inhaled salbutamol was not decreased during salmeterol treatment, except in one patient with asthma worsening over the study year. Baseline finger tremor measured before salbutamol dose-response curves, was significantly lower at the 12-month visit than before treatment was initiated (p < 0.05). Effects of salbutamol on systemic blood pressure, heart rate or finger tremor was not significantly changed during salmeterol treatment. We found a successive and significant decrease in blood eosinophils (p < 0.05) during the 12 months of salmeterol treatment, when the patient with asthma worsening was excluded in the analysis.(ABSTRACT TRUNCATED AT 250 WORDS)
Administration, Inhalation↗